Methods for treatment of polycystic kidney disease
Inventors
Androsavich, John R. • Chau, B. Nelson • Patel, Vishal D.
Assignees
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Publication Number
US-10633657-B2
Publication Date
2020-04-28
Expiration Date
Abstract
Provided herein are methods for the treatment of poly-cystic kidney disease, including autosomal dominant polycystic kidney disease, using modified oligonucleotides targeted to miR-17.
Core Innovation
The invention provides a method of treating polycystic kidney disease by administering to a subject in need thereof a compound comprising a modified oligonucleotide complementary to miR-17. The modified oligonucleotide consists of 8 to 25 linked nucleosides and comprises at least one modified nucleoside, and the nucleobase sequence includes 5′-GCACTTTG-3′ (SEQ ID NO: 3), with each T independently selected from T and U.
The problem addressed is the presence and activity of miR-17 in polycystic kidney disease, including autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD). The disclosed concept focuses on using miR-17 targeting to treat polycystic kidney disease and achieve therapeutic effects in the kidney, including downstream clinical and biomarker outcomes.
The document supports that miR-17 targeting provides therapeutic benefit in polycystic kidney disease, including reported reductions in kidney injury and cyst burden. Model evidence described includes anti-miR-17 reducing kidney weight/body-weight ratio and downregulating kidney injury biomarkers (Kim1, Ngal) and blood urea nitrogen (BUN) in a Pkd1/Pkd2 mouse model (Pkhd1/cre;Pkd2F/F), reducing kidney weight/body-weight ratio and cystic index in a Pcy mouse model, and reducing proliferation and cyst count dose-dependently in primary human ADPKD cyst cultures.
Claims Coverage
Only one independent claim is identified in the provided claims list. The independent claim centers on miR-17-complementary modified oligonucleotides with a specified nucleobase sequence and T/U selection, and it recites treating polycystic kidney disease by administering such a compound to a subject in need thereof.
Treating polycystic kidney disease by administering a miR-17-complementary modified oligonucleotide
Administering to a subject in need thereof a compound comprising a modified oligonucleotide consisting of 8 to 25 linked nucleosides, wherein the modified oligonucleotide comprises at least one modified nucleoside.
Nucleobase sequence complementary to miR-17 with SEQ ID NO: 3 and T/U flexibility
The nucleobase sequence of the modified oligonucleotide is complementary to miR-17 and comprises the nucleobase sequence 5′-GCACTTTG-3′ (SEQ ID NO: 3), wherein each T in the nucleobase sequence is independently selected from T and U.
The identified independent claim requires a miR-17-complementary modified oligonucleotide of 8 to 25 linked nucleosides with at least one modified nucleoside and a specific nucleobase sequence including 5′-GCACTTTG-3′ (SEQ ID NO: 3) with each T independently selected as T or U.
Stated Advantages
Reduces total kidney volume (TKV) and/or height-adjusted TKV (HtTKV).
Reduces cyst growth and improves cystic index.
Reduces hypertension.
Reduces fibrosis.
Reduces albuminuria and hematuria.
Reduces kidney injury markers NGAL and KIM-1.
Improves kidney function readouts including kidney biomarkers such as blood urea nitrogen (BUN) and creatinine and improves creatinine clearance and glomerular filtration rate (GFR).
Documented Applications
Treating polycystic kidney disease, including autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD), by administering a miR-17-complementary modified oligonucleotide.
Using primary human ADPKD cyst cultures as an application context for anti-miR-17 effects on proliferation and cyst count.
Using Pkhd1/cre;Pkd2F/F (Pkd1/Pkd2) mouse model and Pcy mouse model as application contexts to evaluate anti-miR-17 effects on kidney weight/body-weight ratio, cystic index, and kidney injury biomarkers.
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